Pancreatic ductal adenocarcinoma (PDAC) is the fourth-leading cause of cancer-related deaths in the United States with metastasis as the major cause of mortality. The vast majority of PDAC patients will present with metastatic disease with the liver representing the most common site of disease spread. During tumor development, primary tumor cells secrete factors that precondition the liver for metastasis. In this process, th liver becomes a pre-metastatic niche that promotes tumor cell seeding and growth. Macrophages are a prominent component of this niche, yet their role in regulating PDAC metastasis is unknown. Within the tumor microenvironment, the Signal Transducer and Activator of Transcription (STAT) 1 and 3 signaling pathways can play a key role in defining macrophage phenotype with anti- and pro-tumor properties, respectively. Preliminary data demonstrate chronic STAT3 signaling in macrophages residing within the pre-metastatic niche in a genetically engineered murine model of PDAC at a stage prior to the development of invasive disease. In addition, preliminary findings using a murine model of liver metastasis reveal a role for macrophages as key regulators of tumor seeding in PDAC. Thus, the central hypothesis of this proposal is that macrophages residing within the pre-metastatic niche acquire a pro-metastatic phenotype that depends on chronic STAT3 signaling beginning early in tumor development. This hypothesis will be pursued through two specific aims. Aim One will investigate the role of macrophages in regulating metastasis using the LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre (KPC) murine model of PDAC and a liver metastasis model involving the intrasplenic injection of PDAC cell lines derived from KPC mice. Aim Two will examine the effect of STAT1 and STAT3 signaling on the capacity of macrophages to regulate metastasis using conditional models of STAT3 expression in macrophages. Studies in this proposal will improve the understanding of pathways regulating metastasis in PDAC and may identify novel therapeutic strategies for the treatment of PDAC. This project will be co-sponsored by two experienced investigators with complementary skill sets in immunology and cancer biology and demonstrated commitment to mentorship.